Pure Red Cell Aplasia and Hypogammaglobulinemia in a Patient with Thymoma

CASE REPORT

Chen-Sung Lin1,2,5, Yuan-Bin Yu3,6, Han-Shui Hsu2,5, Teh-Ying Chou4,5, Wen-Hu Hsu2,6, Biing-Shiun Huang2,6,7* 1Division of Thoracic Surgery, Department of Surgery, Keelung Hospital, Department of Health Executive Yuan, Keelung; 2Division of Thoracic Surgery, Department of Surgery, 3Division of Hematology and Oncology, Department of Internal Medicine, and 4Division of Surgical Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital; 5Clinical Medicine Institute and 6School of Medicine, National Yang-Ming University; 7School of Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C.

Both pure red cell aplasia (PRCA) and hypogammaglobulinemia are rarer conditions than myasthenia gravis (MG) in thymoma patients. Several articles have discussed the relation between PRCA and thymoma or hypogammaglobulinemia and thymoma, and their proper treatments. Instances of both PRCA and hypogammaglobulinemia in a thymoma patient are few and reported sporadically in the literature. We discuss a 46-year-old woman with thymoma and simultaneous PRCA and hypogammaglobulinemia who achieved complete remission from PRCA after perioperative steroid administration and extended thymectomy, and review the literature. [J Chin Med Assoc 2009;72(1):34–38]

Key Words: hypogammaglobulinemia, pure red cell aplasia, thymoma

Introduction immunoglobulin levels, few B cells, abnormal CD4+/ CD8+ T-cell ratios, and CD4 T-cell lymphopenia.1,4 A thymoma is a neoplasm originating from the thymic Thymoma patients with PRCA or hypogammaglobu- epithelium and is the most common tumor of the ante- linemia are rare, while those with both PRCA and rior mediastinum. Approximately 40% of thymoma hypogammaglobulinemia are even rarer. We discuss patients have clinically associated parathymic syndromes, a 46-year-old woman with thymoma, who had simul- with myasthenia gravis (MG) being the most common.1 taneous PRCA and hypogammaglobulinemia, who The others, including pure red cell aplasia (PRCA), achieved complete PRCA remission after perioperative hypogammaglobulinemia (Good’s syndrome), autoim- steroid administration and extended thymectomy. mune disorders and vasculitis, occur in about 5–10% of thymoma patients.2 PRCA is characterized by normocytic anemia, reticulocytopenia and severe erythroid Case Report hypoplasia in the bone marrow but normal myeloid and megakaryocytic cell lineages.3 Although PRCA A pale 46-year-old woman was referred to hematology occurs in only 5% of thymoma patients, thymoma can for progressive palpitations, dizziness and shortness of be found in 50% of PRCA patients.1 This indicates breath for 5 months. The symptoms were exaggerated, that PRCA is rarer than MG in thymoma patients, especially during menstruation. She had also suffered but the relationship between PRCA and thymoma from recurrent canker sores and common colds in the is closer. Thymoma, combined with hypogamma- past years. globulinemia, was first recognized by Dr Robert Routine chest radiography disclosed a mass over Good in 1954. This occurs in approximately 6–11% of the left anterior mediastinal area (Figure 1A). Chest thymoma patients and is characterized by low serum computed tomography (CT) showed the mass to be

*Correspondence to: Dr Biing-Shiun Huang, Department of Surgery, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, R.O.C. E-mail: [email protected] ● Received: March 12, 2008 ● Accepted: August 27, 2008

A B

Figure 1. (A) Chest radiography shows a huge mass lesion over the left anterior mediastinal area. (B) Chest computed tomography demonstrates a soft tissue mass measuring 7.0 × 4.5 × 8.4 cm with homogeneous enhancement in the left anterior mediastinum.

Positive antinuclear (1:320) and anti-DS-DNA antibodies (55 IU/mL) were detected, but anti-Smith and anti-cardiolipin IgM antibodies were not found. All indicated an aberration in immunologic conditions. In addition, low IgG (675 mg/dL; normal range, 751– 1,560), low IgA (41 mg/dL; normal range, 82–453) and low C3 (59 mg/dL; normal range, 79–152) were noted. These led to the suspicion of hypogammaglobulinemia. The woman was diagnosed with thymoma combined with both PRCA and hypogammaglobulinemia. Preoperatively, she was treated with intravenous dexamethasone 5 mg every 12 hours for 14 days, then with intravenous methylprednisolone 1,000 mg during the operation, and then with oral prednisolone 5 mg twice a day for 1 month after operation. Median sternotomy was done for extended thymectomy. This Figure 2. Bone marrow biopsy: there is severe erythroid hypoplasia showed a yellow-white mass that measured 7.5 × × associated with normal myeloid series (Wright’s stain, 1,000 ). 5.5 × 3.5 cm over the left lobe of the thymus (Figure 3A). Microscopically, the tumor invaded into but not 7.0 × 4.5 × 8.4 cm in size (Figure 1B). Ultrasound- through the fibrous capsule and was composed of guided percutaneous fine needle biopsy was performed, spindle cells with foci rich in lymphocytes, compatible and the pathologist confirmed a diagnosis of thymoma. with thymoma WHO type AB, in Masaoka stage I Even with mild elevation of AChR-Ab (1.37 nmole/L; (Figure 3B).5 normal range < 0.5), neurologists ruled out MG due The patient’s hematologic readings are illustrated in to negative clinical symptoms and signs. Blood tests Figure 4. Complete remission from PRCA was achieved revealed severe normocytic anemia with a red cell count and maintained for at least 3 years. Chest CT also of 2.17 × 106/μL, hemoglobin of 5.0 g/dL and retic- demonstrated no tumor recurrence. Her perioperative ulocyte count of 0.09%, but normal white blood cell immunologic changes are listed in Table 1. Her white and platelet counts. Normal serum bilirubin, serum cell count (1 year after operation) was 4,680 (1/μL), haptoglobin, and urine hemosiderin levels ruled out with lymphocyte percentage of 42%. The lymphocyte the possibility of hemolysis. Serum levels of vitamin subpopulations were CD3 of 73%, CD4 of 30%, CD8 B12, folic acid, ferritin and total iron binding capacity of 40%, and CD19 of 8%. The patient did not totally were all within normal limits. Thus, bone marrow biopsy recover from hypogammaglobulinemia. Clinically, she was done, showing severe erythroid hypoplasia with has had no severe infection postoperatively till now. normal myeloid and megakaryocytic cell lineages. PRCA But the canker sores have recurred and continue to was diagnosed (Figure 2). bother her.

J Chin Med Assoc • January 2009 • Vol 72 • No 1 35 C.S. Lin, et al

A B

Figure 3. (A) Gross appearance: a yellowish-white mass lesion about 7.5 × 5.5 × 3.5 cm in size located over the left lobe of the thymus. (B) Microscopic picture shows a tumor in which foci have features of type A thymoma mixed with foci rich in lymphocytes (hematoxylin & eosin, 400×).

40 Red cell count (M/μL) 35 Hemoglobin (g/dL) Hematocrit (%) 30 Reticulocyte count (%) Peripheral reticulocyte 25 production index (‰)

0 −14 14 42 70 98 126 154 182 Time course (d)

Preoperative Postoperative Hematological conditions 14 d 14d 28d 6mo 1yr 3yr

Red cell count (M/μL) 2.17 3.58 3.56 5.16 4.9 5.13 Hemoglobin (g/dL) 5.0 10.7 10.9 15.5 14.6 15.6 Hematocrit (%) 15.7 32.6 34.5 47.0 45.6 45.7 Reticulocyte count (%) 0.09 2.74 4.69 0.66 – – PRPI (‰) 0.10 13.23 23.97 6.89 – –

PRPI = peripheral reticulocyte production index (normal range: 5–15‰) = (patient’s hematocrit (%)/45) × reticulocyte count × (1/correction shift factor of maturation time).

Figure 4. Perioperative changes in hematologic condition.

36 J Chin Med Assoc • January 2009 • Vol 72 • No 1 Thymoma with both PRCA and hypogammaglobulinemia

Table 1. Perioperative changes in clinical manifestation and profile

Clinical signs/antibody titers/immunoglobulin levels

Oral ulcer Common cold ANA DS-DNA (IU/mL) IgG (mg/dL) IgA (mg/dL) CD4 (%) CD8 (%)

Preoperative Yes Yes 1:320 55 675 41 – – Postoperative Yes No 1:160 Negative 608 8.99 30 40

Discussion There are only a few reports discussing the coexistence of PRCA and hypogammaglobulinemia in thymomic PRCA, either congenital or acquired, is a disease that patients in the literature.13–16 The definite mechanism selectively disturbs erythropoiesis.6 Acquired PRCA between thymoma, PRCA and hypogammaglobuline- is further divided into primary and secondary. Pri- mia is still obscure. mary PRCA has no suspicious causative disease or The relationship between thymoma histologic type drug, and sometimes shows autoantibodies to eryth- and PRCA is also not clear. Masaoka et al reported roblasts or erythropoietins, or is a disorder of lym- that 17 thymoma patients with PRCA were all of the phocytes relating to erythropoiesis. For example, spindle type, in contrast to the polygonal cell types in there may be an increase in T-cell suppression that myasthenic thymomas.17 But Kuo and Shih doubted inhibits erythropoiesis.6 Secondary PRCA, however, the findings because none of their 5 thymoma patients has some suspicious causes, such as thymoma, malig- with PRCA were of the spindle type. This included nant lymphoma, chronic leukemia, systemic lupus 2 with type B1 thymoma, 2 with type B2 thymoma erythematosus (SLE), and Sjögren’s syndrome. Among and 1 with type AB thymoma (new WHO classifica- them, thymoma is the most common.7,8 Thymoma tion).18 All 17 patients reported by Masaoka et al might produce suppressor T-cells or serum thymic might be type A thymoma according to the histologic factor that inhibits erythroid differentiation, but the findings of spindle type thymoma. Our case was stage definite inhibitors have not yet been identified.9–11 I type AB thymoma, characterized by foci having fea- The inhibitors may decay after extended thymectomy; tures of type A thymoma mixed with foci rich in lym- its course can be reflected by peripheral reticulocyte phocytes. For thymoma patients with PRCA and production index (PRPI) increase (Figure 4). From hypogammaglobulinemia, typical histologic types 14 days before to 14 days after surgery, PRPI in our have not yet been reported. In the 17 thymoma patient increased 132-fold, from 0.1‰ to 13.2‰. patients reported by Masaoka et al, 3 had hypogam- This implies an inhibitor drop in the circulation and maglobulinemia. They were all spindle cell thymomas adequate compensated erythropoiesis in the bone (WHO, type A), different from our case. This dis- marrow. Further detection of inhibitors of eryth- crepancy could be due to a lack of consensus in the ropoietin or erythroid progenitor in the future is histologic classification of thymoma and the low case recommended. number. Thymoma with hypogammaglobulinemia was first Treatments for thymoma patients with PRCA, described by Dr Robert Good in 1954, and termed hypogammaglobulinemia or both are also diverse. For Good’s syndrome. It becomes obvious in the 4th or 5th thymoma patients, extended thymectomy is the best decades of life, and most patients suffer from recur- choice of treatment if the thymoma is resectable. For rent sinopulmonary, bacterial urinary tract and skin thymoma patients with PRCA, the complete PRCA infections. Serum shows hypogammaglobulinemia, few remission rate after extended thymectomy is about B-cells, an abnormal CD4+/CD8+ ratio and CD4 30%.17,19,20 But Kuo and Shih doubted the effects of cell lymphopenia.4 In our case, IgG and IgA were low, surgery, because none of their patients improved after even after extended thymectomy (Table 1). Moreover, surgery.18 Adjuvant therapy using immunosuppres- B and CD4+ T lymphocytes were few and accounted sive agents might be necessary to achieve complete for 8% and 30% of total leukocytes, respectively. A remission.17,18 One month of perioperative steroids reversed CD4+ over CD8+ T lymphocyte ratio of 0.75 plus extended thymectomy led to complete remission was also noted. Good’s syndrome does not entirely in our case. The surgical effects on hypogammaglob- improve after treatment. ulinemia were varied.17 There are no studies on surgical According to Jeunet in 1965, 35% of Good’s resection or multimodal treatments in thymoma patients syndrome patients also had pure red cell anemia.12 with hypogammaglobulinemia in the English literature.

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Extended thymectomy plus intravenous immunoglob- 8. Havard CW, Scott RB. Thymic tumour and erythroblastic ulin replacement might be a choice for treating thy- aplasia: report of three cases and a review of the syndrome. Br J Haematol 1960;6:178–90. moma and altering hypogammaglobulinemia to reduce 9. Lahiri TK, Agrawal D, Agrawal K, Shukla J. Pure red cell aplasia 21 infection. associated with thymoma. Indian J Chest Dis Allied Sci 2002; Few have discussed the relationships between PRCA, 44:259–62. thymoma and hypogammaglobulinemia. Treatment 10. Zoumbos NC, Gascon P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. modalities are still controversial. Based on our case and N Engl J Med 1985;312:257–65. others, it is hypothesized that some kind of inhibitor 11. Peschle C, Marmont AM, Marone G, Genovese A, Sasso GF, in the thymoma or thymus itself might precipitate the Condorelli M. Pure red cell aplasia: studies on an IgG serum pathogenesis of PRCA.9–11 Even after extended thymec- inhibitor neutralizing erythropoietin. Br J Haematol 1975;30: tomy, previously released inhibitors still circulate in 411–7. 12. Jeunet F. Thymoma and immunoglobin deficiency syndrome. the serum and need time to decay and be eliminated. Schweiz Med Wochenschr 1965;95:1419–20. Before average or range of time to decay, adjuvant 13. Sato M, Nagai H, Kurasima A, Yotsumoto H, Mohri M, steroid therapy might be necessary. Intravenous immu- Tanaka K, Fukushima K, et al. Lung abscess in a patient with noglobulin replacement therapy is still controversial, Good’s syndrome and pure red cell aplasia. Nihon Kokyuki Gakkai Zasshi 1998;36:187–91. except when there are serious signs of infection. Our 14. Kawamura M, Sawafuji M, Hangai N, Yamamoto T, Kakizaki experience suggests that both extended thymectomy T, Kobayashi T, Kato R, et al. Multidisciplinary treatment for and immunosuppressive therapy may play key roles in a patient with recurrent thymoma associated with myasthenia patients with thymoma who have both PRCA and gravis (MG), pure red cell aplasia (PRCA), and hypogammaglobulinemia. Kyobu Geka 1993;46:1161–5. hypogammaglobulinemia, but further understanding 15. Fujimura S, Ohnuki T, Tanida T, Kondo T, Yamauchi A, and improvement in the management of hypogamma- Handa M, Okabe T, et al. Surgery of thymoma associated with globulinemia are necessary. pure red cell aplasia (PRCA) and hypogammaglobulinemia. Kyobu Geka 1982;35:800–4. 16. Murray WD, Webb JN. Thymoma associated with hypogammaglobulinemia and pure red cell aplasia. Am J Med 1966; References 41:974–80. 17. Masaoka A, Hashimoto T, Shibata K, Yamakawa Y, Nakamae K, 1. Rosenow EC 3rd, Hurley BT. Disorders of the thymus. A review. Iizuka M. Thymomas associated with pure red cell aplasia: Arch Intern Med 1984;144:763–70. histologic and follow-up studies. Cancer 1989;64:1872–8. 2. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the 18. Kuo T, Shih LY. Histologic types of thymoma associated with art. J Clin Oncol 1999;17:2280–9. pure red cell aplasia: a study of five cases including a composite 3. Ammus SS, Yunis AA. Acquired pure red cell aplasia. Am J tumor of organoid thymoma associated with an unusual lipofi- Hematol 1987;24:311–26. broadenoma. Int J Surg Pathol 2001;9:29–35. 4. Kelleher P, Misbah SA. What is Good’s syndrome? Immunological 19. Zeok JV, Todd EP, Dillon M, DeSimone P, Utley JR. The role abnormalities in patients with thymoma. J Clin Pathol 2003; of thymectomy in red cell aplasia. Ann Thorac Surg 1979;28: 56:12–6. 257–60. 5. Rosai J. Histological typing of tumours of the thymus. In: World 20. Hirst E, Robertson TI. The syndrome of thymoma and ery- Health Organization. International Histological Classification throblastopenic anemia. A review of 56 cases including 3 case of Tumors. Berlin: Springer-Verlag, 1999:9–15. reports. Medicine (Baltimore) 1967;46:225–64. 6. Krantz SB. Diagnosis and treatment of pure red cell aplasia. 21. Tarr PE, Sneller MC, Mechanic LJ, Economides A, Eger CM, Med Clin North Am 1976;60:945–58. Strober W, Cunningham-Rundles C, et al. Infections in patients 7. Schmid JR, Kiely JM, Harrison EG Jr, Bayrd ED, Pease GL. with immunodeficiency with thymoma (Good’s syndrome): Thymoma associated with pure red-cell agenesis: review of report of 5 cases and review of the literature. Medicine (Baltimore) literature and report of 4 cases. Cancer 1965;18:216–30. 2001;80:123–33.

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